This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named xe2x80x9ccyclooxygenase-2 (COX-2)xe2x80x9d or xe2x80x9cprostaglandin G/H synthase IIxe2x80x9d) provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
Substituted biphenyl compounds have been reported as components in photographic materials. U.S. Pat. No. 5,238,790, to Shimura et al., describes the use of biphenyl compounds as dispersion agents in photographic materials. U.S. Pat. No. 5,294,530, to Seto et al., describes photographic materials containing biphenyl compounds as anti-fading agents.
U.S. Pat. No. 4,990,647, to Himmler et al., describes a method for the preparation of unsymmetric biaryl compounds.
Substituted biphenyl compounds have been reported as having activity as angiotensin II antagonists. Heterocyclo-substituted biphenyl compounds are described by D. Kim, et al. [Bioorg. Med. Chem. Lett., 4, 41-44 (1994)]. U.S. Pat. No. 5,254,546, to Ardecky et al., describes tetrazole substituted biphenyl compounds. U.S. Pat. No. 5,240,928, to Allen et al., describes aminosulfonyl-substituted biphenyl compounds.
Recently, a terphenyl compound has been described as an anti-inflammatory agent [R. Copeland et al., Med. Chem. Res., 5, 384-393 (1995)].
A class of compounds useful in treating inflammation-related disorders is defined by Formula I: 
wherein A is selected from aryl and heteroaryl, wherein A is optionally substituted with one or more radicals selected from alkyl, halo, alkoxy, alkylthio, cyano, haloalkyl, amino, alkylamino, carboxyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl and mercapto; wherein each of R1 through R4 is independently selected from hydrido, halo, and alkoxy; and wherein each of R5 through R9 is independently selected from hydrido, alkyl, halo, alkoxy, alkylthio, cyano, haloalkyl, amino, alkylamino, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl, mercapto, aminosulfonyl and alkylsulfonyl; or a pharmaceutically-acceptable salt thereof.
Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin-related conditions such as psoriasis, eczema, burns and dermatitis. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention or treatment of cancer, such as colorectal cancer. Compounds of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin""s disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet""s syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The compounds would also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis, conjunctivitis, and of acute injury to the eye tissue. The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders such as Alzheimer""s disease and dementia. The compounds of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and central nervous system damage resulting from stroke, ischemia and trauma.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to, horses, dogs, cats, sheep and pigs.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatories, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.
Suitable LTB4 inhibitors include, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024, 264086 and 292728, ONO compound ONO-LB457, Searle compound SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469, and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930, SC-50605 and SC-51146, and SKandF compound SKF-104493. Preferably, the LTB4 inhibitors are selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumo compound TMK-688.
Suitable 5-LO inhibitors include, among others, masoprocol, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.
The present invention preferably includes compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-l. Preferably, the compounds have a cyclooxygenase-2 IC50 of less than about 0.2 xcexcm, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-l inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC50 of greater than about 1 xcexcM, and more preferably of greater than 10 xcexcM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
A preferred class of compounds consists of those compounds of Formula I wherein A is selected from phenyl, naphthyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein A is optionally substituted with one or more radicals selected from lower alkyl, halo, lower alkoxy, lower alkylthio, cyano, lower haloalkyl, amino, lower alkylamino, lower dialkylamino, lower haloalkoxy, lower hydroxyalkyl, lower alkoxyalkyl, hydroxyl and mercapto; wherein each of R1 through R4 is independently selected from hydrido and halo; or wherein R2 and R3 together form xe2x80x94O(CH2)nOxe2x80x94; wherein n is 1 or 2, inclusive; and wherein each of R5 through R9 is independently selected from hydrido, lower alkyl, halo, lower alkoxy, lower alkylthio, cyano, lower haloalkyl, amino, lower alkylamino, lower dialkylamino, lower haloalkoxy, lower hydroxyalkyl, lower alkoxyalkyl, hydroxyl, mercapto, aminosulfonyl and lower alkylsulfonyl; or a pharmaceutically-acceptable salt thereof.
A more preferred class of compounds consists of those compounds of Formula I wherein A is selected from phenyl, naphthyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein A is optionally substituted with one or more radicals selected from lower alkyl, halo, lower alkoxy, lower haloalkyl and lower dialkylamino; wherein each of R1 through R4 is independently selected from hydrido and halo; or wherein R2 and R3 together form xe2x80x94O(CH2)nOxe2x80x94; wherein n is 1 or 2, inclusive; wherein each of R5, R6, R8 and R9 is hydrido; and wherein R7 is selected from aminosulfonyl and lower alkylsulfonyl; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a subclass of compounds which consists of compounds wherein A is selected from phenyl, naphthyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein A is optionally substituted with one or more radicals selected from lower alkyl, halo, lower alkoxy, lower haloalkyl and lower dialkylamino; wherein each of R1 through R4 is independently selected from hydrido and halo; or wherein R2 and R3 together form xe2x80x94OCH2Oxe2x80x94; and wherein R7 is aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula I wherein A is selected from phenyl, thienyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl and pyridyl, wherein A is optionally substituted with one or more radicals selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, methylenedioxy, ethylenedioxy, fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, dichloroethyl, dichlorofluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloropropyl, N-ethyl-N-methylamino, N,N-dimethylamino and N,N-diethylamino; wherein each of R1 through R4 is independently selected from hydrido, fluoro, chloro and bromo; or wherein R2 and R3 together form xe2x80x94OCH2Oxe2x80x94; wherein R5, R6, R8 and R9 are hydrido; and wherein R7 is aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a second subclass of compounds of high interest wherein A is selected from phenyl, naphthyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein A is optionally substituted with one or more radicals selected from lower alkyl, halo, lower alkoxy, lower haloalkyl and lower dialkylamino; wherein each of R1 through R4 is independently selected from hydrido and halo; or wherein R2 and R3 together form xe2x80x94OCH2Oxe2x80x94; and wherein R7 is lower alkylsulfonyl; or a pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula I wherein A is selected from phenyl, thienyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl and pyridyl, wherein A is optionally substituted with one or more radicals selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, methylenedioxy, ethylenedioxy, fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, dichloroethyl, dichlorofluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloropropyl, N-ethyl-N-methylamino, N,N-dimethylamino and N,N-diethylamino; wherein each of R1 through R4 is independently selected from hydrido, fluoro, chloro and bromo; or wherein R2 and R3 together form xe2x80x94OCH2Oxe2x80x94; wherein R5, R6, R8 and R9 are hydrido; and wherein R7 is methylsulfonyl; or a pharmaceutically-acceptable salt thereof.
A family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:
4-(2-biphenyl)benzenesulfonamide;
4-[2-(3-methylphenyl) phenyl]benzenesulfonamide;
4-[2-(3-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-chlorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-(4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,4-dimethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-methoxy-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(4-methyl-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-methylphenyl]phenyl]benzenesulfonamide;
4-[2-(4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(4-methoxy-3-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,4-dimethoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(4-methoxy-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-methoxyphenyl]phenyl]benzenesulfonamide;
4-[2-(4-fluorophenyl)phenyl]benzenesultonamide;
4-[2-(4-fluoro-3-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(4-fluoro-3-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3,4-difluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-fluoro-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-fluorophenyl]phenyl]benzenesulfonamide;
4-[2-(4-chlorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,4-dichlorophenyl)phenyl]benzenesulfonamide; 4-[2-(4-chloro-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[4-chloro-3-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-(4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-methyl-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-methoxy-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[3,4-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-trifluoromethylphenyl]phenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-methylphenyl]phenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-methoxyphenyl]phenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-fluorophenyl]phenyl]benzenesulfonamide;
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-trifluoromethylphenyl]phenyl]benzenesulfonamide;
4-[2-[3,4-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-(3,5-dimethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-difluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichlorophenyl)phenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-(3,4,5-trimethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxy-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-difluoro-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)-4-methylphenyl]phenyl]benzenesulfonamide;
4-[2-[-3,5-di(N,N-dimethylamino)-4-methylphenyl]phenyl]benzenesulfonamide;
4-[2-(3,5-dimethyl-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3,4,5-trimethoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-difluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)-4-methoxyphenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]phenyl]benzenesulfonamide;
4-[2-(3,5-dimethyl-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxy-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,4,5-trifluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)-4-fluorophenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]phenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-dimethylphenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-dimethoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-difluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,4,5-trichlorophenyl)phenyl]benzenesulfonamide;
4-[2-[4-chloro-3,5-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[2-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-(3,5-dimethyl-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxy-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-difluoro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[3,4,5-tri(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)-4-trifluoromethylphenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-difluoro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[2-[3,4,5-tri(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-(6-phenyl-1,3-benzodioxol-5-yl)benzenesulfonamide;
4-[6-(3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-chlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4-dimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-fluoro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-chloro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-methoxy-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-methyl-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3-(N,N-dimethylamino)-4-methylphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-methoxy-3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-fluoro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-chloro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4-dimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-methoxy-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[(3-(N,N-dimethylamino)-4-methoxyphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-fluoro-3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4-difluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-chloro-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-fluoro-3-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-fluoro-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3-(N,N-dimethylamino)-4-fluorophenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chloro-3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chloro-3-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4-dichlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chloro-3-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chloro-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-chloro-3-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-methyl-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-fluoro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-chloro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-methoxy-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,4-di(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3-(N,N-dimethylamino)-4-trifluoromethylphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)-3-methylphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)-3-fluorophenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3-chloro-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)-3-methoxyphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)-3-trifluoromethylphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,4-di(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-difluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dichlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4,5-trimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-difluoro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dichloro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dimethoxy-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(trifluoromethyl)-4-methylphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(N,N-dimethylamino)-4-methylphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dimethyl-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-difluoro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dichloro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4,5-trimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(trifluoromethyl)-4-methoxyphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4,5-trimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-difluoro-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dichloro-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dimethoxy-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(trifluoromethyl)-4-fluorophenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chloro-3,5-dimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chloro-3,5-difluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4,5-trichlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(4-chloro-3,5-dimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-chloro-3,5-di(trifluoromethyl)pheny]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dimethyl-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-difluoro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dichloro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dimethoxy-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,4,5-tri(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-di(N,N-dimethylamino)-4-trifluoromethylphenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)-3,5-difluorophenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[3,4,5-tri(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[(4,5-difluoro-2-biphenyl)benzenesulfonamide; 4-[4,5-difluoro-2-(3-methylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-chlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-methoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methylphenyl)phenyl]benzenesulfonamide;
4-(4,5-difluoro-2-(3,4-dimethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-fluoro-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methylphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-methoxy-4-methylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methyl-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-methylphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methoxy-3-methylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-fluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4-dimethoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methoxy-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-methoxyphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluorophenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluoro-3-methylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4-difluorophenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-chloro-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluoro-3-methoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluoro-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-fluorophenyl]phenyl]benzenesulfonamide;
4-[2-(4-chlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methylphenyl)-4,5-difluorophenyl]benzenesultonamide;
4-[2-(4-chloro-3-fluorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(3,4-dichlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-trifluoromethylphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-[4-chloro-3-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-(trifluoromethyl)phenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-methyl-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-fluoro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-trifluoromethylphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-methoxy-4-(trifluoromethyl)phenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,4-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-trifluoromethylphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-methylphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-fluorophenyl]phenyl]benzenesulfonamide;
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-methoxyphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,4-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-difluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4,5-trimethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-difluoro-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-methylphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethoxy-4-methylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-methylphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)-4-methylphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethyl-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-difluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4,5-trimethoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-methoxyphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethyl-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4,5-difluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-fluorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethoxy-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-fluorophenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]phenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-dimethylphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-difluorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4,5-trichlorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-dimethoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-[4-chloro-3,5-di(trifluoromethyl)phenyl]-4,5-difluorophenyl]benzenesulfonamide;
4-[2-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethyl-4-(trifluoromethyl)phenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-difluoro-4-(trifluoromethyl)phenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-(trifluoromethyl)phenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethoxy-4-(trifluoromethyl)phenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,4,5-tri(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)-4-(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-difluoro-4-(N,N-dimethylamino phenyl]phenyl]benzenesulfonamide;
4-[2-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[3,4,5-tri(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-(3,4,5,6-tetrafluoro-2-biphenyl)benzenesulfonamide;
4-[2-(3-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonalide;
4-[2-(3-chlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[3,4,5,6-tetrafluoro-2-(3-(trifluoromethyl)phenyl)phenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,4-dimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-methoxy-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-methyl-3-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-methylphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-methyl-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,4-dimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-methoxy-3-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-methoxyphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-fluoro-3-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,4-difluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-chloro-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-fluoro-3-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-fluoro-3-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-fluorophenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-chlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,4-dichlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-trifluoromethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-chloro-3-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[3,4,5,6-tetrafluoro-2-[4-(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
4-[2-(3-methyl-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-chloro-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3-methoxy-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,4-di(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3-(N,N-dimethylamino)-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-methylphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-fluorophenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-methoxyphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)-3-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,4-di(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-difluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dichlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,4,5-trimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-difluoro-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-methylphenyl) 3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxy-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)-4-methylphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)-4-methylphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethyl-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-difluoro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)-4-methoxyphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethyl-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,4,5-trifluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxy-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)-4-fluorophenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-dimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-difluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[3,4,5,6-tetrafluoro-2-(3,4,5-trichlorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-dimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-chloro-3,5-di(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethyl-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(3,5-dimethoxy-4-(trifluoromethyl)phenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,4,5-tri(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(N,N-dimethylamino)-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-difluoro-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,5-di(trifluoromethyl)-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-[3,4,5-tri(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
4-[2-(4-hydroxymethylphenyl)phenyl]benzenesulfonamide;
4-[2-(4-methylthiophenyl)phenyl]benzenesulfonamide;
4-[2-(4-cyanophenyl)phenyl]benzenesulfonamide;
4-[2-(4-aminophenyl)phenyl]benzenesulfonamide;
4-[2-(4-hydroxyphenyl)phenyl]benzenesulfonamide;
4-[2-[4-(N-methylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-(4-methoxymethylphenyl)phenyl]benzenesulfonamide;
4-[2-(1,3-benzodioxol-5-yl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(5-methylpyridin-2-yl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(6-methylpyridin-3-yl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(2-thienyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-furyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-hydroxymethylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methylthiophenyl)phenyl]benzenesulfonamide;
4-[2-(4-cyanophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-aminophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-hydroxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N-methylamino)phenyl]phenyl]benzenesulfonamide; and
4-[4,5-difluoro-2-(4-methoxymethylphenyl)phenyl]benzenesulfonamide.
A second family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:
2-[4-(methylsulfonyl)phenyl]-1-phenylbenzene;
1-(3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4-dimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3-methoxy-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3-fluoro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3-chloro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3-methyl-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4-dimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
2-fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-fluoro-3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-fluoro-3-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4-difluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl benzene;
1-(4-chloro-3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-chloro-3-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-chloro-3-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4-dichlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-difluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dichlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4,5-trimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dimethoxy-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-difluoro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dichloro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dimethyl-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4,5-trimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-difluoro-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dichloro-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dimethyl-4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dimethoxy-4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4,5-trifluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,5-dichloro-4-fluorophenyl)-2-[4-(methylsulfonyl) phenyl]benzene;
1-(4-chloro-3,5-dimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-chloro-3,5-dimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-chloro-3,5-difluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(3,4,5-trichlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
6-[4-(methylsulfonyl)phenyl]-5-phenyl-1,3-benzodioxole;
5-(3-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4-dimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-fluoro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-chloro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-methoxy-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-methyl-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-fluoro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4-dimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-fluoro-3-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4-difluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-fluoro-3-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-chloro-3-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-chloro-3-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4-dichlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-chloro-3-methoxyphenyl)-6-(4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-difluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dichlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4,5-trimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-difluoro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dichloro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dimethoxy-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dimethyl-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-difluoro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4,5-trimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dimethyl-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4,5-trifluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dichloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,5-dimethoxy-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-chloro-3,5-dimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-chloro-3,5-difluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(3,4,5-trichlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
5-(4-chloro-3,5-dimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole; 1,2-difluoro-5-[4-(methylsulfonyl)phenyl]-4-phenylbenzene;
1,2-difluoro-4-(3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3-chlorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3-chloro-4-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3-methoxy-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(4-methoxy-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3-chloro-4-methoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,4-dimethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3-chloro-4-fluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(4-fluoro-3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(4-chlorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
4-(4-chloro-3-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
4-(4-chloro-3-fluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3,4-dichlorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
4-(4-chloro-3-methoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-dimethylphenyl-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-difluorophenyl)-5-[(4-(methylsulfonyl)phenyl]benzene;
4-(3,5-dichlorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-dimethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,4,5-trimethylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-difluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3,5-dichloro-4-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-dimethoxy-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-dimethyl-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3,5-dichloro-4-methoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,4,5-trimethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3,5-dimethyl-4-fluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,4,5-trifluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(3,5-dichloro-4-fluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,5-dimethoxy-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(4-chloro-3,5-dimethylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
4-(4-chloro-3,5-difluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(3,4,5-trichlorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
4-(4-chloro-3,5-dimethoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene;
5-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-1,3-benzodioxole;
2-chloro-4-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-N,N-dimethylbenzenamine;
6-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-2,3-dihydro-1,4-benzodioxin;
1,2-dichloro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
2-[4,5-difluoro-4xe2x80x2-(methylsulfonyl)-(1,1xe2x80x2-biphenyl)-2-yl]-5-methylpyridine;
5-[4,5-difluoro-4xe2x80x2-(methylsulfonyl)-(1,1xe2x80x2-biphenyl)-2-yl]-2-methylpyridine; and
1,2-difluoro-5-[4-(methylsulfonyl)phenyl]-4-(2-thiazolyl) benzene.
Within Formula I there is a subclass of compounds of high interest represented by Formula II: 
wherein A is selected from 
wherein each of R2 and R3 is independently selected from hydrido and halo; or wherein R2 and R3 together form xe2x80x94OCH2Oxe2x80x94; wherein each of R10 through R14 is independently selected from hydrido, lower alkyl, halo, lower alkoxy, lower haloalkyl, and lower dialkylamino; or wherein R11 and R12 together form xe2x80x94O(CH2)nOxe2x80x94; wherein n is 1-2, inclusive; and wherein R7 is selected from lower alkylsulfonyl and aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a second subclass of compounds of high interest represented by Formula III: 
wherein each of R11 through R13 is independently selected from hydrido, halo, lower alkoxy, lower haloalkyl, amino, lower alkylamino, lower dialkylamino, and lower haloalkoxy; or wherein R11 and R12 together form xe2x80x94O(CH2)nOxe2x80x94; wherein n is 1-2, inclusive; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a third subclass of compounds of high interest represented by Formula IV: 
wherein Y is CR11 or N; wherein Z is CR10 or N; wherein each of R10 through R12 is independently selected from hydrido and lower alkyl; wherein R7 is aminosulfonyl or methylsulfonyl; provided one of Y and Z is N; or a pharmaceutically-acceptable salt thereof.
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (xe2x80x94CH2xe2x80x94) radical. Where the term xe2x80x9calkylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9calkylsulfonylxe2x80x9d, it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine atoms. The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihaloalkyl and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. xe2x80x9cLower haloalkylxe2x80x9d embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term xe2x80x9chydroxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are xe2x80x9clower hydroxyalkylxe2x80x9d, radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The term xe2x80x9calkoxyxe2x80x9d embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, tert-butoxy, methylenedioxy and ethylenedioxy. The term xe2x80x9calkoxyalkylxe2x80x9d embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxyalkyl radicals are xe2x80x9clower alkoxyalkylxe2x80x9d radicals having one to six carbon atoms and one or two alkoxy radicals. Examples of such radicals include methoxymethyl, methoxyethyl, ethoxyethyl, methoxybutyl and methoxypropyl. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d and xe2x80x9clower haloalkoxyxe2x80x9d radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term xe2x80x9cheterocyclicxe2x80x9d embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3-nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The term xe2x80x9cheteroarylxe2x80x9d embraces unsaturated heterocyclic radicals. Examples of heteroaryl radicals include unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Preferred heteroaryl radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, pyrazolyl, isoxazolyl, pyrrolyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are xe2x80x9clower alkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The terms xe2x80x9csulfamyl,xe2x80x9d xe2x80x9caminosulfonylxe2x80x9d and xe2x80x9csulfonamidylxe2x80x9d denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (xe2x80x94SO2NH2). The terms xe2x80x9ccarboxyxe2x80x9d or xe2x80x9ccarboxylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9ccarboxyalkylxe2x80x9d, denotes xe2x80x94CO2H. The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term xe2x80x9calkylaminoxe2x80x9d denotes amino groups which have been substituted with one or two alkyl radicals forming N-alkylamino and N,N-dialkylamino radicals, respectively. Preferred alkylamino radicals are xe2x80x9clower alkylaminoxe2x80x9d having alkyl portions of one to six carbon atoms. Examples include N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.
The present invention comprises a pharmaceutical composition for the treatment of inflammation or an inflammation-associated disorder, such as arthritis, comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a therapeutic method of treating inflammation or an inflammation-associated disorder in a subject, the method comprising treating a subject having or susceptible to such inflammation or inflammation-associated disorder with a therapeutically-effective amount of a compound of Formula I.
Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, xcex2-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made from N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
General Synthetic Procedures
The compounds of the invention can be synthesized according to the following procedures of Schemes I-XIX, wherein the R1-R14 substituents are as defined for Formulas I-IV, above, except where further noted. U.S. patent application Ser. No. 08/346,433 is incorporated by reference. 
Synthetic Scheme I shows the three step procedure for the preparation of the prerequisite substituted phenylboronic acids 1 and 2 from commercially available phenyl bromides. In step one, halogen-metal interchange in THF at xe2x88x9278xc2x0 C. generates the corresponding organolithium reagents. In step two, the organolithium species are reacted with trimethyl borate to give the corresponding methyl esters. In step three, hydrolysis with aqueous sodium hydroxide provides the substituted phenylboronic acids 1 and 2, respectively. 
Synthetic Scheme II shows an alternative three step procedure for the preparation of the prerequisite substituted phenylboronic acids 1 and 2 from commercially available phenyl bromides. In step one, reaction with magnesium metal in THF at reflux in the presence of an iodine catalyst generates the corresponding Grignard reagents. In step two, the Grignard reagents are reacted with trimethyl borate to give the corresponding methyl esters. In step three, hydrolysis with aqueous sodium hydroxide provides the substituted phenylboronic acids 1 and 2, respectively. 
Synthetic Scheme III shows the procedure for the preparation of the substituted 2-bromo-biphenyl intermediates 3 from commercially available 1,2-dibromobenzenes and the appropriate substituted phenylboronic acid 1 (prepared in Synthetic Schemes I and II). Using a coupling procedure similar to the one developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)], 1,2-dibromobenzenes are reacted with 1 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate to give the corresponding substituted 2-bromobiphenyl intermediates 3. 
Synthetic Scheme IV shows the procedure for the preparation of the substituted 2-bromobiphenyl intermediates 4 from commercially available 1,2-dibromobenzenes and the appropriate substituted phenylboronic acids 2 (prepared in Synthetic Schemes I and II). Using a coupling procedure similar to the one developed by Suzuki et al. (synthetic Scheme III), 1,2-dibromobenzenes are reacted with 2 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis (triphenylphosphine)palladium(0), and 2M sodium carbonate to give the corresponding substituted 2-bromobiphenyl intermediates 4. 
Synthetic Scheme V shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 5 from 2-bromo-biphenyl intermediates 3 (prepared in Synthetic Scheme III) and the appropriate substituted phenylboronic acids 2 (prepared in Synthetic Schemes I and II). Using a coupling procedure similar to the one developed by Suzuki et al. (Synthetic Scheme III), intermediates 3 are reacted with 2 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate to give the corresponding 1,2-diarylbenzene antiinflammatory agents 5 of this invention. 
Synthetic Scheme VI shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 5 from 2-bromo-biphenyl intermediates 4 (prepared in Synthetic Scheme IV) and the appropriate substituted phenylboronic acids 1 (prepared in Synthetic Schemes I and II). Using a coupling procedure similar to the one developed by Suzuki et al. (Synthetic Scheme III), intermediates 4 are reacted with 1 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate to give the corresponding 1,2-diarylbenzene antiinflammatory agents 5 of this invention. 
Synthetic Scheme VII shows an alternative one step procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 5 from commercially available 1,2-dibromobenzenes and the appropriate substituted phenylboronic acids 1 and 2 (prepared in Synthetic Schemes I and II). Using a coupling procedure similar to the one developed by Suzuki et al. (Synthetic Scheme III), an equimolar mixture of 1,2-dibromobenzenes, 1 and 2 are reacted in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate to give the corresponding 1,2-diarylbenzene antiinflammatory agents 5 of this invention. 
Synthetic Scheme VIII shows the three step procedure for the preparation of the 2-aryl-phenylboronic acids 6 and 7 from corresponding 2-bromobiphenyl intermediates 3 (prepared in Synthetic Scheme III) and 4 (prepared in Synthetic Scheme IV), respectively. In step one, halogen-metal interchange in THF at xe2x88x9278xc2x0 C. generates the corresponding organolithium reagents. In step two, the organolithium species are reacted with trimethyl borate to give the corresponding methyl esters. In step three, hydrolysis with aqueous sodium hydroxide provides the substituted phenylboronic acids 6 and 7, respectively. 
Synthetic Scheme IX shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 5 from commercially available substituted phenyl bromides and 2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII). Using a coupling procedure similar to the one developed by Suzuki et al. (Synthetic Scheme III), substituted phenyl bromides are reacted with 6 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate to give the corresponding 1,2-diarylbenzene antiinflammatory agents 5 of this invention. 
Synthetic Scheme X shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 5 from commercially available substituted phenyl bromides and 2-aryl-phenylboronic acids 7 (prepared in Synthetic Scheme VIII). Using a coupling procedure similar to the one developed by Suzuki et al. (Synthetic Scheme III), substituted phenyl bromides are reacted with 7 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine) palladium(0), and 2M sodium carbonate to give the corresponding 1,2-diarylbenzene antiinflammatory agents 5 of this invention. 
Synthetic Scheme XI shows the procedure for the preparation of 3-bromopyridines 9 from commercially available pyridines 8. Using a procedure similar to the one developed by Reitz et al. [U.S. Pat. No. 5,155,177], pyridines 8 are reacted with bromine in the presence of aluminum chloride to give the 3-bromopyridines 9. 
Synthetic Scheme XII shows the procedure for the preparation of pyridyltin intermediates 10 from 3-bromopyridines 9 (prepared in Synthetic Scheme XI). In step one, halogen-lithium interchange in THF at xe2x88x9278xc2x0 C. generates the corresponding organolithium reagents. In step two, the organolithium species are reacted with trimethyltin chloride to give the corresponding pyridyltin intermediates 10. 
Synthetic Scheme XIII shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 11 from 2-bromo-biphenyl intermediates 3 (prepared in Synthetic Scheme III) and the appropriate substituted pyridyltin intermediates 10 (prepared in Synthetic Scheme XII). Reaction of 3 with 10 in toluene at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium (0) gives the corresponding 1,2-diarylbenzene antiinflammatory agents 11 of this invention. 
Synthetic Scheme XIV shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 13 from 2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII) and commercially available bromopyridines 12. Reaction of 6 with 12 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium (0) and 2M sodium carbonate gives the corresponding 1,2-diarylbenzene antiinflammatory agents 13 of this invention. 
Synthetic Scheme XV shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 15 from 2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII) and commercially available 2-bromofuran 14. Reaction of 6 with 14 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium (0) and 2M sodium carbonate gives the corresponding 1,2-diarylbenzene antiinflammatory agents 15 of this invention. 
Synthetic Scheme XVI shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 17 from 2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII) and commercially available 3-bromofuran 16. Reaction of 6 with 16 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium (0) and 2M sodium carbonate gives the corresponding 1,2-diarylbenzene antiinflammatory agents 17 of this invention. 
Synthetic Scheme XVII shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 19 from 2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII) and commercially available 2-bromothiophene 18. Reaction of 6 with 18 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium (0) and 2M sodium carbonate gives the corresponding 1,2-diarylbenzene antiinflammatory agents 19 of this invention. 
Synthetic Scheme XVIII shows the procedure for the preparation of 1,2-diarylbenzene antiinflammatory agents 21 from 2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII) and commercially available 3-bromothiophene 20. Reaction of 6 with 20 in toluene/ethanol at reflux in the presence of a Pd0 catalyst, e.g., tetrakis(triphenylphosphine)palladium (0) and 2M sodium carbonate gives the corresponding 1,2-diarylbenzene antiinflammatory agents 21 of this invention. 
Synthetic Scheme XIX shows the three step procedure for the preparation of sulfonamide antiinflammatory agents 23 from their corresponding methyl sulfones 22. Using a procedure similar to the one developed by Huang et al. [Tetrahedron Lett., 35, 7201 (1994)], THF solutions of the methyl sulfones 22 at xe2x88x9278xc2x0 C. are treated with base, e.g., n-BuLi, n-C3H7 MgCl, etc., to generate the corresponding carbanions. In step two, the anions are treated with an organoborane, e.g., triethylborane, tributylborane, etc., at xe2x88x9278xc2x0 C. and warmed to ambient temperature prior to stirring at reflux. An alternative to the boron chemistry involves room temperature alkylation, such as with haloalkyltrialkylsilanes, followed by treatment with silylalkyl-elimination agents. In step three, an aqueous solution of sodium acetate and hydroxyamine-O-sulfonic acid is added to provide the corresponding sulfonamide antiinflammatory agents 23 (5 where R12xe2x95x90SO2NH2) of this invention.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I-IV. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. HRMS is an abbreviation for High resolution mass spectrometry. The term xe2x80x9cNDxe2x80x9d signifies xe2x80x9cnot determined.xe2x80x9d All NMR data are from 1H NMR unless otherwise indicated.